Abstract: FR-PO358

SOX9 Is a Critical Regulator of Extracellular Matrix Deposition during Kidney Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis


  • Raza, Sayyid M ammar, University of Manchester, Manchester, United Kingdom
  • Pritchett, James P, Manchester Metropolitan University, Manchester, United Kingdom
  • Hanley, Neil, University of Manchester, Manchester, United Kingdom
  • Kalra, Philip A., Salford Royal Hospital NHS Trust, Salford, United Kingdom
  • Piper hanley, Karen, University of Manchester, Manchester, United Kingdom

Renal fibrosis is a major cause of morbidity and mortality and a common feature of most chronic kidney disease (CKD). It is characterised by extracellular matrix (ECM) secretion from effector cells (myofibroblasts) resulting in tissue dysfunction and scarring. Discovering how to block scar production represents a very attractive therapeutic avenue for much needed antifibrotic drug development.


Primary pericytes were extracted from wild type mice. Cells were analysed by immunohistochemistry, western blotting and qPCR. Kidney fibrosis was induced in vivo by 2 week unilateral ureteric obstruction (UUO). SOX9-loss was achieved through tamoxifen injections of Sox9fl/fl; RosaCreERT2 mice. Fibrosis was assessed histologically in mice and human kidney fibrotic tissue.


In wild type fibrotic kidneys SOX9 was increased and detected in α-SMA positive cells, demarcating activated myofibroblasts, along with collagen type 1 (COL1) rich fibrotic tracts disrupting normal tissue. In vitro, primary mouse pericytes expressed nuclear SOX9 surrounded by α-SMA. SOX9 knockdown in activated pericytes using RNA interference caused a commensurate reduction in COL1 protein expression (~60%), whereas the pro-fibrotic cytokine transforming growth factor-beta (TGF-β) induced expression of SOX9 by 2.5 fold in pericytes and 2.3 fold in the rat fibroblast cell line, NRK-49F. To model the stiffening environment of fibrotic kidneys we cultured pericytes on 1, 4 and 12 KPa hydrogels where α-SMA, SOX9 and the mechanosensitive factor YAP1 became robustly expressed at 12KPa. Moreover, YAP1 was also increased in UUO kidneys.
To support a role for SOX9 in kidney fibrosis, following UUO-fibrosis mice lacking SOX9 had significantly reduced fibrosis by picrosrius red quantification (35% reduction) and α-SMA positive myofibroblasts were reduced by 45%. Importantly, in various human kidney diseases (Membranous nephropathy, Diabetic nephropathy, IgA nephropathy) fibrotic areas were associated with SOX9 positivity histologically.


These data support a pro-fibrotic role for SOX9 (similar to other organs) in kidney fibrosis where it is regulated by TGF-β and the mechnosignalling factor YAP1. Moreover, this provides an interesting opportunity for inhibiting SOX9 or its dependent pathways for anti-fibrotic therapy.